Kinetics of nicotinic acetylcholine ion channels in the presence of intravenous anaesthetics and induction agents

Abstract

6 We conclude that these agents are not altering channel properties merely by exerting non-specific effects via the lipid bilayer and that they are probably not all acting by similar mechanisms.

Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones

“…Unlike a charged blocker that can access a binding site via the channel pore, propofol probably diffuses into the membrane and binds to a hydrophobic region of the protein or a site located at the lipid-protein interface. Interestingly, propofol modulation of the GABAA receptor demonstrates similar slow kinetics (rate of association: 3 x 105 M-1 s'1) suggesting that binding of propofol to a hydrophobic site modulates the gating of both excitatory and inhibitory amino acid receptors (Wachtel & Wegrzynowicz, 1992;Dilger et al, 1994 (Dilger et al, 1994 (Adams, 1976 (a+ k+B [C]) (Colquhoun & Hawkes, 1983). Furthermore, the time course of inhibition of the macroscopic current (ron) is determined by l/Po (x+k+B [C]), where PO is the probability that the channels are in the open state.…”

“…For example, the post-operative dreams, mood disturbances, and hallucinations observed following propofol anaesthesia, are more commonly associated with the dissociative anaesthetic ketamine (Young, 1988;Suresh, 1991;Oxorn et al, 1994). Propofol also blocks several non-ligand gated channels and exerts opposing actions on excitatory and inhibitory neurotransmitter receptors (Frenkel & Urban, 1991;Hales & Lambert, 1992;Magnelli et al, 1992;Veintemilla et al, 1992;Wachtel & Wegrzynowicz, 1992, Baum 1993Hara et al, 1993;Dilger et al, 1994;Olcese et al, 1994;Orser et al, 1994). Modulation of these receptors might also contribute to the clinical properties of propofol.…”

Identification of Binding Sites in the Nicotinic Acetylcholine Receptor for [3H]Azietomidate, a Photoactivatable General Anesthetic

“…R(ϩ)-Etomidate, one of the most potent general anesthetics used clinically, acts at micromolar concentrations both as an anesthetic and as a potentiator of the responses to submaximal concentrations of GABA, whereas at concentrations above 10 M, it inhibits GABA responses and directly activates GABA A receptors (8), and it inhibits nAChRs (9). GABA A receptors containing ␤ 2 or ␤ 3 , but not ␤ 1 , subunits are most sensitive to etomidate, and site-directed mutagenesis has identified a single amino acid within the M2 segment that determines etomidate sensitivity in GABA A receptors in vitro (10) and for etomidate anesthesia in vivo (11,12).…”

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

“…Ketamine is also an antagonist of NMDA receptors in rat cortex (Harrison & Simmonds, 1985) and blocks these receptors at sub-clinical concentrations, by acting both as a use-dependent open channel blocker (Honey et al, 1985) and through allosteric inhibition (Orser et al, 1997). Ketamine inhibits the response to acetylcholine or nicotine in both muscle and neuronal type nAChRs (Sumikawa et al, 1983;Wachtel & Wegrzynowicz, 1992;Scheller et al, 1996;Durieux, 1995;Furuya et al, 1999;Flood & Krasowski, 2000;Friederich et al, 2000;Sasaki et al, 2000;Yamakura et al, 2000). In the case of nAChRs containing the a4 subunit, inhibition occurs at concentrations similar to those e ective in inhibiting NMDA responses (Flood & Krasowski, 2000;Friederich et al, 2000;Sasaki et al, 2000).…”